Cystic fibrosis is a disease caused by mutations in the CFTR gene (or Cystic Fibrosis Transmembrane Conductance Regulator Protein). In the lung, the mutated CFTR gene results in a non-functioning CFTR protein, which leads to the formation of sticky mucus that acts as a reservoir of bacteria, which in turn promotes cycles of infection and ultimately irreversible and life limiting lung damage. Gene therapy aims to deliver a functioning CFTR gene to the respiratory epithelium and correct the defect that causes sticky mucus.

However, although the disease cause and symptoms are easily described, generating a gene therapy drug that reverses the symptoms has been hugely challenging. Our lungs are designed to remove foreign material and keep the airspaces clear for efficient gas exchange. Therefore, drug developers have to develop solutions that overcome the efficient clearance mechanisms to ensure the gene therapy reaches the target cells (airway epithelial) and that the CFTR protein is correctly expressed in the target cell. At the same time, drug developers also have to work to prevent an inflammatory response to the gene therapy drug as an immune response would be detrimental to the patient and would clear the drug from the lungs prior to any therapeutic benefit.

In the current multi-dose trial, patients were administered the functioning CFTR gene in a non-viral vector (a plasmid) in combination with a liposome vector (known as GL67A). This non-viral gene therapy was developed by the UK consortium to maximise lung delivery and expression of the CFTR gene while limiting the inflammatory response. The team also demonstrated that this so called therapeutic DNA/lipid complex could be efficiently administered to patients by the inhaled route to ensure maximum dose to the target organ.

Multi-dose gene therapy clinical trial in cystic fibrosis patients

One hundred and forty patients were recruited to the multi-dose trial and randomly assigned to receive placebo (62 patients) or the therapeutic DNA/lipid complex (78 patients.) The trial was conducted double blinded so that neither the patients nor the investigators knew who received the gene therapy or the placebo. The patients were given 12 treatments over the course of one year. Data from the trial demonstrated that patients administered the gene therapy had a significant, albeit modest, improvement in lung function assessment (termed FEV1) compared with patients administered the placebo. In addition, and as expected, there were no treatment related adverse events between the two patients groups.

Preclinical inhalation studies

The Inhalation facility at Charles River Edinburgh played a small part in this success story. We performed the GLP preclinical safety evaluation study for the multi-dose clinical trial.[2] In this preclinical safety study mice were exposed to the aerosolised gene therapy in a lipid complex on 12 dose occasions and as per the planned multidose trial. The results demonstrated that the novel gene therapy reached the lungs in a consistent and dose-dependent manner without any adverse effects – key data for regulatory approval in patients.

Next steps for the UK Cystic Fibrosis Consortium

It has taken many years for the dedicated team (of over 80 researchers) to get to this stage of efficacy evaluation in cystic fibrosis patients and the results are hugely encouraging. However, as the lead investigator (Eric Alton) commented back in 2012, when he compared this trial to the Wright brothers historic flight from Kitty Hawk, NC., the team has shown it is possible to treat the underlying genetic fault but their work is only the first step in a process to correct the faulty gene. The team believe that the future lies in the use of viral vectors to ensure long term lung expression of the CTFR protein and clinical trials are planned with therapeutic viral vectors in 2017.